期刊
NATURE MEDICINE
卷 21, 期 4, 页码 363-+出版社
NATURE RESEARCH
DOI: 10.1038/nm.3822
关键词
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资金
- Swedish Research Council
- Family Erling-Persson Foundation
- Heinrich Heine University Dusseldorf
- German Center for Diabetes Research
- German Diabetes Center
- Federal Ministry of Health
- Ministry for Innovation, Science and Research of North Rhine-Westphalia
- Ipsen Pharma GmbH
- Anton-Betz Foundation
- European Regional Development Fund
- German Research Foundation [La1216/6-1]
- Competence Network Diabetes Mellitus from the Federal Ministry for Education and Research
- JDRF [31-2008-416]
- NIDDK-funded Integrated Islet Distribution Program (IIDP) at City of Hope
- MRC [MR/L02036X/1] Funding Source: UKRI
- Wellcome Trust [101033/C/13/Z] Funding Source: Wellcome Trust
- Medical Research Council [MR/L02036X/1] Funding Source: researchfish
- Wellcome Trust [101033/C/13/Z] Funding Source: researchfish
In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca2+ concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.
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